Food deprivation is a variable that has recently emerged as a major factor controlling drug-rewarded behavior. The finding that even a small reduction in the food ration more than doubles drug intake has been extended to several species, routes of administration and all major classes of drugs abused by humans. Recent clinical reports have indicated a relationship between fasting or dieting and increased drug use and relapse to smoking. These findings have considerable significance with regard to the initiation, maintenance, termination and prevention of drug abuse; however, further research is needed. A major objective of the proposed research is to further investigate the food deprivation phenomenon using an animal model. Chronically catheterized rats will be trained to press a lever to receive intravenous injections of cocaine and other drugs. A second major objective is to study factors related to the initiation and persistence of cocaine-rewarded behavior. Sensitive animal models that have been developed in this laboratory will be used to study behavioral predisposing factors, behavioral dependence on cocaine, cocaine withdrawal and relapse to cocaine-seeking behavior. Almost all of the proposed experiments incorporate these two major goals. Specific aims are: 1) to further investigate behavioral and physiological mechanisms in an attempt to explain the large increases in drug-rewarded behavior produced by food deprivation; 2) to test the effects of food deprivation on the discriminative stimulus properties of drugs, extending the generality of the phenomenon beyond the self-administration paradigm; 3) to explore the mechanisms involved in naltrexone-induced increases in cocaine-reinforced behavior and the interaction with feeding conditions; 4) to compare the acquisition and maintenance of cocaine-reinforced behavior as a function of feeding conditions and genotype; 5) to develop an animal model of behavioral dependence on and withdrawal from cocaine self-administration, and to study its prevention and reversal by administration of cocaine and other drugs; 6) to use an animal model of relapse to cocaine-seeking behavior to examine the role of behavioral and pharmacological (e.g., antidepressant medications) interventions in the reinstatement of cocaine-seeking behavior.